JAMA Revisits FDA's Controversial OK of Depression Drug Gepirone

A new analysis published in JAMA Psychiatry is raising fresh questions about how FDA evaluates drug efficacy when clinical trial results are mixed, using the decades-long regulatory journey of the antidepressant Exxua (gepirone) extended release as a case study. In a Special Communication published 6/24, researchers examined the FDA's review of Fabre-Kramer Pharmaceutical’s gepirone ER, which was eventually approved in 2023 for major depressive disorder despite a clinical development program that included far more negative trials than positive ones.

According to the authors, FDA's efficacy assessment was based on 13 studies, including 12 acute treatment trials and one relapse-prevention study. Only two of the acute trials demonstrated statistically significant superiority over placebo, while the remaining studies failed to show a benefit. In three trials, FDA reviewers found evidence that gepirone performed worse than an active comparator.

The mixed evidence led FDA reviewers to reject the drug's application four times between 1999 and 2007. The agency repeatedly expressed concerns that the two positive studies could have represented chance findings and cited the substantial amount of negative evidence in the program.

The application's trajectory changed after sponsor Fabre-Kramer Pharmaceuticals filed a formal dispute-resolution request in 2014, prompting review by senior FDA leadership. Although an FDA advisory committee voted in 2015 that efficacy had not been established, agency leaders ultimately concluded that the two positive studies were sufficient to satisfy the statutory standard for demonstrating effectiveness. The drug was subsequently approved.

The authors argue that the case illustrates the FDA's use of "regulatory flexibility" when evaluating conflicting clinical evidence and highlights a broader shift in drug approvals. They note that only about half of recent FDA approvals have been supported by two or more adequate and well-controlled trials, the traditional benchmark often associated with demonstrating efficacy.

The paper also raises concerns that physicians and patients may overestimate the benefits of FDA-approved drugs, particularly when labeling and public communications emphasize positive studies while providing less visibility into unsuccessful trials.

As a result, the authors call for greater transparency in FDA-approved product labeling. Specifically, they recommend that labels summarize the results of all adequate and well-controlled trials conducted for an approved indication, including negative studies, rather than focusing primarily on trials that support approval.

The analysis arrives as FDA continues to face scrutiny over its use of regulatory flexibility in drug approvals and as policymakers debate how much evidence should be required to demonstrate clinical benefit. The gepirone case, the authors contend, offers a rare window into how agency leadership can weigh statistical significance, clinical relevance, and conflicting evidence when making approval decisions.